Methods of using (+)-1,4-dihydro-7-[(3s,4s)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid in combination therapy

ABSTRACT

Methods of treating, preventing or managing cancers are disclosed. The methods encompass the administration of SNS-595 in combination with a second active agent. In certain embodiments, the method of treatment comprise administering SNS-595 in combination with cisplatin, carboplatin, gemcitabine or a combination thereof.

This application claims the benefit of priority of U.S. provisionalapplication No. 60/981,766, filed Oct. 22, 2007, the contents of whichare hereby incorporated by reference in their entirety.

1. FIELD

Provided herein are specific dosing regimens for treating, preventing ormanaging cancers with certain amounts of enantiomerically pure(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid in combination with certain amounts of a second anti-cancer agentor a combination of second agents. In certain embodiments, the methodsencompass treating, preventing or managing solid tumors. It should benoted that the combinations or cocktails encompass simultaneous as wellas sequential administration.

In one embodiment, the combination therapy comprises administering acertain amount of(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid, or a pharmaceutically acceptable salt, solvate or hydrate thereofthereof and a certain amount of one or more second agent selected fromcarboplatin, cisplatin, and gemcitabine administered in particularcycles for specific cancers.

2. BACKGROUND

SNS-595 is chemically named(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid, and has the following structure:

SNS-595 is known for its anti-tumor activity. Treatment of the followingcancers with SNS-595 has been proposed in the literature: bladdercancer, breast cancer, cervical cancer, colon cancer, esophageal cancer,head and neck cancer, liver cancer, lung cancer, melanoma, myeloma,neuroblastoma (i.e., CNS cancer), ovarian cancer, pancreatic cancer,prostate cancer, renal cancer, sarcoma, skin cancer, stomach cancer,testicular cancer, thyroid cancer, hematological cancer and uterinecancer. Various dosing regimens have been reported, for example, see,U.S. Patent Application Pub. Nos. 2005-0203120; 2005-0215583,2006-0025437, and 2008-0063642 and International Publication No. WO2007/028171, all of which are incorporated herein by reference in theirentirety.

There continues to be a need for safe and effective dosages and dosingregimens for administering SNS-595 in treating, preventing and managingvarious cancers

3. SUMMARY

Provided herein are methods of treating, preventing or managing cancers,including, but not limited to bladder cancer, breast cancer, cervicalcancer, colon cancer (including colorectal cancer), esophageal cancer,head and neck cancer, liver cancer, lung cancer (both small cell andnon-small cell), melanoma, myeloma, neuroblastoma (i.e., CNS cancer),ovarian cancer, pancreatic cancer, prostate cancer, renal cancer,sarcoma (including osteosarcoma), skin cancer (including squamous cellcarcinoma), stomach cancer, testicular cancer, thyroid cancer, anduterine cancer. The cancer can be relapsed, refractory and/or resistantto conventional therapy.

The methods comprise administering to a subject a therapeutically orprophylactically effective amount of SNS-595, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof thereof in combination witha second agent. In one embodiment, the second agent is selected from thegroup consisting of carboplatin, cisplatin, gemcitabine, andcombinations thereof.

In one embodiment, the combination therapy comprises administeringSNS-595, or a pharmaceutically acceptable salt, solvate or hydratethereof thereof and carboplatin. In one embodiment, the combinationtherapy comprises administering SNS-595, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof thereof and cisplatin. Inone embodiment, the combination therapy comprises administering SNS-595,or a pharmaceutically acceptable salt, solvate or hydrate thereofthereof and gemcitabine. Also provided are dosing regimens, dosingschedules and methods of using SNS-595, or a pharmaceutically acceptablesalt, solvate or hydrate thereof thereof in combination with the secondagents.

In one embodiment, the methods provided include the administration ofSNS-595, or a pharmaceutically acceptable salt, solvate or hydratethereof thereof in combination with about 5 mg/m² to about 200 mg/m²cisplatin. For example, one embodiment includes administration ofcisplatin at a dose of about 50 or 70 mg/m² once every 3 to 4 weeks. Oneembodiment includes administration of cisplatin at a dose of about 50 or70 mg/m² once every 3 weeks. Another embodiment includes administrationof cisplatin at a dose of about 75 or 100 mg/m² once every 3 weeks. Inanother embodiment, administration of cisplatin is at a dose of about 20mg/m² daily for up to 5 days. The administration of cisplatin can bemade by intravenous infusion, intravenous push, bolus injection orsubcutaneous injection. In one embodiment, the administration ofcisplatin is once every 3 to 4 weeks, while the administration ofSNS-595 occurs once per week for three weeks or once every three weeks.In one embodiment, the administration of cisplatin is daily for 5 days,while the administration of SNS-595 occurs once per week for three weeksor once every three weeks. In one embodiment, the administration ofcisplatin is once a week for 3 weeks, while the administration ofSNS-595 occurs once per week for three weeks or once every three weeks.

In one embodiment, the methods provided include the administration ofSNS-595, or a pharmaceutically acceptable salt, solvate or hydratethereof thereof in combination with about 50 mg/m² to about 400 mg/m²carboplatin. For example, one embodiment includes administration ofcarboplatin at a dose of about 300 or about 360 mg/m² once every 3weeks. One embodiment includes administration of carboplatin at a doseof about 300 or 360 mg/m² once every 4 weeks. The administration ofcarboplatin can be made by intravenous infusion, intravenous push, bolusinjection or subcutaneous injection. In one embodiment, theadministration of carboplatin is once every 3 weeks, while theadministration of SNS-595 occurs once per week for three weeks or onceevery three weeks. In one embodiment, the administration of carboplatinis once a week for 3 weeks, while the administration of SNS-595 occursonce per week for three weeks or once every three weeks.

In one embodiment, the methods provided include the administration ofSNS-595, or a pharmaceutically acceptable salt, solvate or hydratethereof thereof in combination with about 100 mg/m ² to about 1500 mg/m²gemcitabine. For example, one embodiment includes administration ofgemcitabine at a dose of about 1000 or 1250 mg/m² once every week for atleast 4 weeks. The administration of gemcitabine can be made byintravenous infusion, intravenous push, bolus injection or subcutaneousinjection. In one embodiment, the administration of gemcitabine is oncea week for up to 4 weeks, while the administration of SNS-595 occursonce per week for three weeks or once every three weeks. In oneembodiment, the administration of gemcitabine is twice a week for 2weeks, while the administration of SNS-595 occurs once per week forthree weeks.

As discussed herein, the administration of SNS-595 and the second agentsas set forth above in a week is considered a weekly cycle. The methodscontemplate performing one weekly cycle, optionally waiting a period ofone week to several weeks where neither the second agent nor SNS-595 isgiven, then repeating a weekly cycle. The methods also contemplaterepeating the weekly cycles continuously, for example, for 3 to 5 weeks.In addition, the methods contemplate repeating the cycle for severalcycles, waiting a period of a week to several weeks where neitherSNS-595 nor the second agent is given then repeating one or more cycles.Finally, the methods provide administration of a SNS-595/second agentweekly cycle followed by a cycle of only the second agent or SNS-595.

4. BRIEF DESCRIPTION OF DRAWINGS

FIG. 1: provides the effect of treatment with(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid (SNS-595) and cisplatin on tumor volume in an ovarian cancerxenograft model (treatment with SNS-595 is indicated with black arrowsand cisplatin with gray arrows);

FIG. 2: provides the effect of treatment with(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid (SNS-595) and cisplatin on % body weight change in an ovariancancer xenograft model; (treatment with SNS-595 is indicated with blackarrows and cisplatin with gray arrows);

FIG. 3 provides the effect of treatment with(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid (SNS-595) and cisplatin on % suvival in an ovarian cancer xenograftmodel;

FIG. 4: provides the effect of treatment with(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid (SNS-595) and carboplatin on tumor volume in a non small cell lungcancer xenograft model (treatment with SNS-595 is indicated with blackarrows and carboplatin with gray arrows);

FIG. 5: provides the effect of treatment with(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid (SNS-595) and carboplatin on % body weight change in a non smallcell lung cancer xenograft model (treatment with SNS-595 is indicatedwith black arrows and carboplatin with gray arrows);

FIG. 6: provides the effect of treatment with(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid (SNS-595) and carboplatin on % survival in a non small cell lungcancer xenograft model;

FIG. 7: provides the effect of treatment with(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid (SNS-595) and gemcitabine on tumor volume in a non small cell lungcancer xenograft model (treatment with SNS-595 is indicated with blackarrows and gemcitabine with gray arrows);

FIG. 8: provides the effect of treatment with(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid (SNS-595) and gemcitabine on % survival in a non small cell lungcancer xenograft model (treatment with SNS-595 is indicated with blackarrows and gemcitabine with gray arrows);

FIG. 9: provides the effect of treatment with(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid (SNS-595) and gemcitabine on % body weight change in a non smallcell lung cancer xenograft model;

FIG. 10: provides the effect of treatment with(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid (SNS-595) and gemcitabine on the tumor volume in a pancreaticcancer xenograft model (treatment with SNS-595 is indicated with blackarrows and gemcitabine with gray arrows);

FIG. 11: provides the effect of treatment with(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid (SNS-595) and gemcitabine on % survival in a pancreatic cancerxenograft model (treatment with SNS-595 is indicated with black arrowsand gemcitabine with gray arrows); and

FIG. 12: provides the effect of treatment with(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid (SNS-595) and gemcitabine on % body weight change in a pancreaticcancer xenograft model.

In the figures, 595 refers to(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid (SNS-595).

5. DETAILED DESCRIPTION OF THE INVENTION

Provided herein are methods of treating, managing, or preventing cancerscomprising administering to a subject, such as a mammal in need of suchtreatment, management or prevention a therapeutically orprophylactically effective amount of SNS-595, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof thereof in combination witha second agent selected from carboplatin, cisplatin, and gemcitabine. Inone embodiment, the methods encompass treating, preventing or managingvarious cancers selected from bladder cancer, breast cancer, cervicalcancer, colon cancer (including colorectal cancer), esophageal cancer,head and neck cancer, liver cancer, lung cancer (both small cell andnon-small cell), melanoma, myeloma, neuroblastoma (i.e., CNS cancer),ovarian cancer, pancreatic cancer, prostate cancer, renal cancer,sarcoma (including osteosarcoma), skin cancer (including squamous cellcarcinoma), stomach cancer, testicular cancer, thyroid cancer, anduterine cancer. The cancer can be relapsed, refractory or resistant toconventional therapy.

In the methods provided herein, SNS-595, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof thereof is administered incombination with a second active agent selected from carboplatin,cisplatin and gemcitabine. Specific doses and dosing regimens for thesecombinations are provided below.

5.1 Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications are incorporated by reference in their entirety. In theevent that there are a plurality of definitions for a term herein, thosein this section prevail unless stated otherwise.

As used herein, enantiomerically pure(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid is substantially free from(−)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid (i.e., in enantiomeric excess). In other words, the “(+)” form of1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid is substantially free from the “(−)” form of the compound and is,thus, in enantiomeric excess of the “(−)” form. The term“enantiomerically pure” or “pure enantiomer” denotes that the compoundcomprises more than 75% by weight, more than 80% by weight, more than85% by weight, more than 90% by weight, more than 91% by weight, morethan 92% by weight, more than 93% by weight, more than 94% by weight,more than 95% by weight, more than 96% by weight, or more than 97% byweight of the enantiomer.

As used herein and unless otherwise indicated, the term“enantiomerically pure(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid” refers to at least about 80% by weight(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid and at most about 20% by weight(−)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid, at least about 90% by weight(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid and at most about 10% by weight the (−)-enantiomer, at least about95% by weight(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid and at most about 5% by weight the (−)-enantiomer, at least about97% by weight(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid and at most about 3% by weight (−)-enantiomer.

As used herein and unless otherwise indicated, the terms “treat,”“treating” and “treatment” refer to alleviating or reducing the severityof a symptom associated with the disease or condition being treated.

The term “prevention” includes the inhibition of a symptom of theparticular disease or disorder. In some embodiments, patients withfamilial history of cancer or leukemia are candidates for preventiveregimens. Generally, the term “preventing” refers to administration ofthe drug prior to the onset of symptoms, particularly to patients atrisk of cancer.

As used herein and unless otherwise indicated, the term “managing”encompasses preventing the recurrence of the particular disease ordisorder in a patient who had suffered from it, lengthening the time apatient who had suffered from the disease or disorder remains inremission, reducing mortality rates of the patients, and/or maintaininga reduction in severity or avoidance of a symptom associated with thedisease or condition being managed.

As used herein, “subject” is an animal, typically a mammal, including ahuman, such as a human patient.

As used herein, the term “cancer” includes, but is not limited to, solidtumors and blood born tumors. The term “cancer” refers to disease ofskin tissues, organs, blood, and vessels, including, but not limited to,cancers of the bladder, bone or blood, brain, breast, cervix, chest,colon, endrometrium, esophagus, eye, head, kidney, liver, lung, mouth,neck, ovaries, pancreas, prostate, rectum, stomach, testis, throat, anduterus.

The term “relapsed” refers to a situation where patients who have had aremission of cancer after therapy have a return of cancer cells.

The term “refractory or resistant” refers to a circumstance wherepatients, even after intensive treatment, have residual cancer cells intheir body.

As used herein and unless otherwise indicated, the term“pharmaceutically acceptable salt” includes, but is not limited to,salts of acidic or basic groups that can be present in the compoundsprovided herein. Under certain acidic conditions, the compound can forma wide variety of salts with various inorganic and organic acids. Theacids that can be used to prepare pharmaceutically acceptable salts ofsuch basic compounds are those that form salts comprisingpharmacologically acceptable anions including, but not limited to,acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide,calcium edetate, camsylate, carbonate, chloride, bromide, iodide,citrate, dihydrochloride, edetate, edisylate, estolate, esylate,fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate,hexylresorcinate, hydrabamine, hydroxynaphthoate, isethionate, lactate,lactobionate, malate, maleate, mandelate, mesylate, methylsulfate,muscate, napsylate, nitrate, panthothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, succinate, sulfate, tannate,tartrate, teoclate, triethiodide and pamoate. Under certain basicconditions, the compound can form base salts with variouspharmacologically acceptable cations. Non-limiting examples of suchsalts include alkali metal or alkaline earth metal salts and,particularly, calcium, magnesium, sodium, lithium, zinc, potassium andiron salts.

As used herein and unless otherwise indicated, the term “hydrate” meansa compound provided herein or a salt thereof, that further includes astoichiometric or non-stoichiometeric amount of water bound bynon-covalent intermolecular forces.

As used herein and unless otherwise indicated, the term “solvate” meansa solvate formed from the association of one or more solvent moleculesto a compound provided herein. The term “solvate” includes hydrates(e.g., mono-hydrate, dihydrate, trihydrate, tetrahydrate thereof and thelike).

As used herein, and unless otherwise specified, the terms “second agent”or “second active agent” refer to cisplatin, carboplatin or gemcitabineor a combination thereof.

As used herein, and unless otherwise specified, the terms“therapeutically effective amount” and “effective amount” of a compoundrefer to an amount sufficient to provide a therapeutic benefit in thetreatment, prevention and/or management of a disease, to delay orminimize one or more symptoms associated with the disease or disorder tobe treated. The terms “therapeutically effective amount” and “effectiveamount” can encompass an amount that improves overall therapy, reducesor avoids symptoms or causes of disease or disorder, or enhances thetherapeutic efficacy of another therapeutic agent.

The terms “co-administration” and “in combination with” include theadministration of two therapeutic agents (for example, SNS-595 and asecond anti-cancer agent, such as carboplatin, cisplatin, andgemcitabine) either simultaneously, concurrently or sequentially with nospecific time limits. In one embodiment, both agents are present in thecell or in the patient's body at the same time or exert their biologicalor therapeutic effect at the same time. In one embodiment, the twotherapeutic agents are in the same composition or unit dosage form. Inanother embodiment, the two therapeutic agents are in separatecompositions or unit dosage forms.

The term “supportive care agent” refers to any substance that treats,prevents or manages an adverse effect from SNS-595 treatment.

The term “about,” as used herein, unless otherwise indicated, refers toa value that is no more than 10% above or below the value being modifiedby the term. For example, the term “about 10 mg/m²” means a range offrom 9 mg/m² to 11 mg/m².

5.2 SNS-595

The compound for use in the methods and compositions provided herein isenantiomerically pure(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid, which is also known as SNS-595 or AG-7352. SNS-595 has thefollowing chemical structure:

In certain embodiments, pharmaceutically acceptable salts, solvates,hydrates or prodrugs of SNS-595 are used in the methods and compositionsprovided herein.

SNS-595 can be prepared by methods known to one of skill in the art, forexample, according to the preparation procedure for Example C-1 of U.S.Pat. No. 5,817,669, entitled “Compounds, processes for the preparationthereof and anti-tumor agents,” issued Oct. 6, 1998, and in JapanesePatent Application No. Hei 10-173986, to Chikugi et al., which areincorporated herein by reference in their entireties. Certain exemplarypharmaceutical compositions comprising SNS-595 and methods of using thesame are described in U.S. Patent Application Pub. Nos. 2005/0203120;2005/0215583, 2006/0025437, 2006/0063795 and 2006/0247267, and2008-0063642 and International Publication No. WO 2007/028171, which areincorporated herein by reference in their entireties.

5.3 Second Active Agents

In the methods and compositions provided herein, SNS-595 or apharmaceutically acceptable salt, solvate or hydrate thereof thereof canbe used with or combined with second active agents. Without beinglimited by any theory, it is believed that certain combinations worksynergistically in the treatment of cancers. The methods also encompassthe use of SNS-595 or a pharmaceutically acceptable salt, solvate orhydrate thereof thereof in a manner to alleviate, reduce or avoidadverse effects associated with certain second active agents. Alsoprovided are methods, wherein the second active agents are used in themanner to alleviate, reduce or avoid adverse or unwanted effectsassociated with SNS-595 or a pharmaceutically acceptable salt, solvateor hydrate thereof thereof including dose limiting toxicity.

One or more second active ingredients or agents can be used togetherwith SNS-595 in the methods and compositions provided herein. In certainembodiments, the second active agent is selected from carboplatin,cisplatin, and gemcitabine.

In the combination therapy provided herein, SNS-595 and the second agentcan be administered simultaneously or sequentially with SNS-595. Incertain embodiments, SNS-595 and the second agent selected fromcarboplatin, cisplatin, and gemcitabine are used in combination methodsthat may also include the use of one or more other therapies including,but not limited to, treatment with a therapeutic antibody thatspecifically binds to a cancer antigen, hematopoietic growth factor,cytokine, other anti-cancer agent, antibiotic, cox-2 inhibitor,immunomodulatory agent, immunosuppressive agent, corticosteroid or apharmacologically active mutant or derivative thereof, anti-canceragents, radiation therapy, anti-emetics and the like.

In certain embodiments, use of a second active agent in combination withSNS-595 may be modified or delayed during or shortly followingadministration of SNS-595 as deemed appropriate by the practitioner ofskill in the art. In certain embodiments, subjects being administeredSNS-595 in combination with the second agents may receive supportivecare including antiemetics, when appropriate. In some embodiments,subjects being administered SNS-595 in combination with the secondagents may be administered a growth factor as a third active agentaccording to the judgment of the practitioner of skill in the art. Insome embodiments, provided is administration of SNS-595 and the secondagent in combination with erythropoietin or darbepoetin (Aranesp). Incertain embodiments, administration of erythropoietin or darbepoetin isdelayed during administration of SNS-595, the second agent or both. Incertain embodiments, erythropoietin or darbepoetin is administeredduring administration of SNS-595, for instance when the subject presentsanemia or severe anemia. In some embodiments, administration ofprophylactic granulocyte-macrophage colony-stimulating factor (GM-CSF);sargramostim (Leukine®), molgramostim, (Leukomax) or granulocytecolony-stimulating factor (G-CSF); filgrastim (Neupogen®), pegfilgrastim(Neulasta®) is delated during one or more administrations of SNS-595. Incertain embodiments, provided are method for adminstrations ofprophylactic granulocyte-macrophage colony-stimulating factor (GM-CSF);sargramostim (Leukine®), molgramostim, (Leukomax) or granulocytecolony-stimulating factor (G-CSF); filgrastim (Neupogen®), pegfilgrastim(Neulasta®) permitted after administration of SNS-595, for instance in asubject experiencing neutropenia or recurrent neutropenia. In certainembodiments, provided is administration of myeloid growth factors incombination with SNS-595, for instance in a subject with a seriousneutropenic complication, such as tissue infection, sepsis syndrome, orfungal infection, or at the discretion of the practitioner of skill.

In certain embodiments, the methods provided herein further compriseadministration of one or more of the following: oral allopurinol,Rasburicase, Leukapheresis (for istance, administered up to 72 hoursafter the first treatment with SNS-595 Injection), and any othermedication deemed appropriate by the practitioner of skill in the art.

5.4 Methods of Treatment and Prevention

The methods provided herein encompass treating, preventing or managingvarious solid tumors, including, but not limited to, the bladder cancer,breast cancer, cervical cancer, colon cancer (including colorectalcancer), esophageal cancer, head and neck cancer, liver cancer, lungcancer (both small cell and non-small cell), melanoma, myeloma,neuroblastoma (i.e., CNS cancer), ovarian cancer, pancreatic cancer,prostate cancer, renal cancer, sarcoma (including osteosarcoma), skincancer (including squamous cell carcinoma), stomach cancer, testicularcancer, thyroid cancer, and uterine cancer. The methods comprise thestep of administering to the subject a therapeutically effective amountof an enantiomerically pure(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid (SNS-595) or a pharmaceutically acceptable salt, solvate or hydratethereof thereof in combination with a therapeutically effective amountof a second active agent selected from carboplatin, cisplatin andgemcitabine. In one embodiment, the second active agent is gemcitabine.In one embodiment, the second active agent is carboplatin. In oneembodiment, the second active agent is cisplatin.

5.4.1 Combination Therapy with a Second Active Agent

In certain embodiments, the methods provided herein compriseadministering SNS-595 in combination with one or more second activeagents, and further in combination with radiation therapy, therapy withother anti-cancer agents or surgery. The administration of SNS-595 andthe second active agents to a patient can occur simultaneously orsequentially by the same or different routes of administration. Thesuitability of a particular route of administration employed for aparticular active agent will depend on the active agent itself (e.g.,whether it can be administered orally without decomposing prior toentering the blood stream) and the disease being treated. Recommendedroutes of administration for the second active agents are known to thoseof ordinary skill in the art. See, e.g., Physicians' Desk Reference,1755-1760 (56^(th) ed., 2002).

The second active agent may be administered simultaneously, atessentially the same time, or sequentially with SNS-595. Ifadministration takes place sequentially, second active agent may beadministered before or after administration of SNS-595. In someembodiments, the second active agent is administered beforeadministration of SNS-595. In some embodiments, the second active agentis administered simultaneously with administration of SNS-595. In someembodiments, the second active agent is administered after theadministration of SNS-595. SNS-595 and the second active agent need notbe administered by means of the same vehicle. In some embodiments, thesecond active agent and SNS-595 are administered in different vehicles.In embodiments of the methods described herein where delivery of SNS-595and the second active agent are both by an intravenous route ofadministration, administration of each component of the combination neednot be administered in the same IV line. In some embodiments, SNS-595 isadministered in a different IV line than the second active agent. Thesecond active agent may be administered one or more times, and thenumber of administrations of each component of the combination may bethe same or different. In addition, SNS-595 and the second active agentneed not be administered at the same site.

In one embodiment, SNS-595 can be administered in an amount of fromabout 1 to about 150 mg/m², about 1 to about 120 mg/m², about 1 to about100 mg/m², about 1 to about 75 mg/m², about 1 to about 60 mg/m², about 1to about 50 mg/m², about 3 to about 30 mg/m², about 3 to about 24 mg/m²in combination with a second active agent disclosed herein. In anotherspecific embodiment, SNS-595 is administered at a dose of about 10 toabout 90 mg/m².

In another embodiment, the methods provided herein compriseadministering to a patient in need thereof, a dose of about 1 mg/m²-150mg/m² of SNS-595 and a therapeutically effective amount of a secondagent selected from cisplatin, carboplatin and gemcitabine and furtheradministering a therapeutically effective amount of a supportive careagent. Such supportive care agents are known in the art, for example,see, U.S. Application Publication No. 2006/0025437, which isincorporated by reference in its entirety.

In certain embodiments, the combination dosing of SNS-595 and the secondagent is used together as well with supportive care agents or otherauxillary therapies. While not intending to be bound by any particulartheory of operation, it is believed that SNS-595 and the second agentcan act synergistically in the methods provided herein. Exemplary dosingschedules for the combination dosing of SNS-595 and the second agent areprovided below.

5.5 Pharmaceutical Compositions and Dosage Forms

The methods provided herein use pharmaceutical compositions containingSNS-595 and/or a pharmaceutically acceptable salt, solvate or hydratethereof thereof and pharmaceutically acceptable carriers, such asdiluents or adjuvants, or in combination with a second agent. Inclinical practice SNS-595 and/or a pharmaceutically acceptable salt,solvate or hydrate thereof may be administered by any conventionalroute, including but not limited to orally, parenterally, rectally or byinhalation (e.g. in the form of aerosols). In one embodiment, SNS-595and/or a pharmaceutically acceptable salt, solvate or hydrate thereof isadministered by an IV injection.

The compositions for parenteral administration can be emulsions orsterile solutions. Use may be made, as solvent or vehicle, of propyleneglycol, a polyethylene glycol, vegetable oils, in particular olive oil,or injectable organic esters, for example ethyl oleate. Thesecompositions can also contain adjuvants, in particular wetting,isotonizing, emulsifying, dispersing and stabilizing agents.Sterilization can be carried out in several ways, for example using abacteriological filter, by radiation or by heating. They can also beprepared in the form of sterile solid compositions which can bedissolved at the time of use in sterile water or any other injectablesterile medium.

The compositions can also be aerosols. For use in the form of liquidaerosols, the compositions can be stable sterile solutions or solidcompositions dissolved at the time of use in apyrogenic sterile water,in saline or any other pharmaceutically acceptable vehicle. For use inthe form of dry aerosols intended to be directly inhaled, the activeprinciple is finely divided and combined with a water-soluble soliddiluent or vehicle, for example dextran, mannitol or lactose.

Pharmaceutical compositions can be used in the preparation ofindividual, single unit dosage forms. Pharmaceutical compositions anddosage forms comprise SNS-595 and one or more excipients.

Pharmaceutical compositions and dosage forms can also comprise one ormore additional active ingredients. Examples of second, or additional,active ingredients are disclosed herein.

In certain embodiments, a composition provided herein is apharmaceutical composition or a single unit dosage form. Pharmaceuticalcompositions and single unit dosage forms provided herein comprise aprophylactically or therapeutically effective amount of SNS-595, andtypically one or more pharmaceutically acceptable carriers orexcipients. The term “carrier” refers to a diluent, adjuvant (e.g.,Freund's adjuvant (complete and incomplete)), excipient, or vehicle withwhich the therapeutic is administered. Such pharmaceutical carriers canbe sterile liquids, such as water and oils, including those ofpetroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and the like. In certainembodiments, water is a carrier when the pharmaceutical composition isadministered intravenously. Saline solutions and aqueous dextrose andglycerol solutions can also be employed as liquid carriers, particularlyfor injectable solutions. Examples of suitable pharmaceutical carriersare described in Remington: The Science and Practice of Pharmacy,21^(st) edition, Lippincott, Williams and Wilkins, Baltimore, Md.(2005), the contents of which are hereby incorporated by reference intheir entirety.

Typical pharmaceutical compositions and dosage forms comprise one ormore excipients. Suitable excipients are well-known to those skilled inthe art of pharmacy, and non limiting examples of suitable excipientsinclude starch, glucose, lactose, sucrose, gelatin, malt, rice, flour,chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodiumchloride, dried skim milk, glycerol, propylene, glycol, water, ethanoland the like. Whether a particular excipient is suitable forincorporation into a pharmaceutical composition or dosage form dependson a variety of factors well known in the art including, but not limitedto, the way in which the dosage form will be administered to a subjectand the specific active ingredients in the dosage form. The compositionor single unit dosage form, if desired, can also contain minor amountsof wetting or emulsifying agents, or pH buffering agents.

Further provided herein are pharmaceutical compositions and dosage formsthat comprise one or more compounds that reduce the rate by which anactive ingredient will decompose. Such compounds, which are referred toherein as “stabilizers,” include, but are not limited to, antioxidantssuch as ascorbic acid, pH buffers, or salt buffers.

The pharmaceutical compositions and single unit dosage forms can takethe form of solutions, suspensions, emulsion, powders and the like. Suchcompositions and dosage forms will contain a prophylactically ortherapeutically effective amount of a prophylactic or therapeutic agent,in certain embodiments, in purified form, together with a suitableamount of carrier so as to provide the form for proper administration tothe subject. The formulation should suit the mode of administration. Inone embodiment, the pharmaceutical compositions or single unit dosageforms are sterile and in suitable form for administration to a subject,such an animal subject, including a mammalian subject, or in particulara human subject.

A pharmaceutical composition provided herein is formulated to becompatible with its intended route of administration. Examples of routesof administration include, but are not limited to, parenteral, e.g.,intravenous, intradermal, intramuscular, subcutaneous, inhalation,intranasal, transdermal, topical, transmucosal, intra-tumoral,intra-synovial and rectal administration. In a specific embodiment, thecomposition is formulated in accordance with routine procedures as apharmaceutical composition adapted for intravenous, subcutaneous,intramuscular, intranasal or topical administration to human beings. Inone embodiment, a pharmaceutical composition is formulated in accordancewith routine procedures for subcutaneous administration to human beings.Typically, compositions for intravenous administration are solutions insterile isotonic aqueous buffer. Where necessary, the composition mayalso include a solubilizing agent and a local anesthetic such aslignocaine to ease pain at the site of the injection.

Examples of dosage forms include, but are not limited to: liquid dosageforms suitable for parenteral administration to a subject; and sterilesolids (e.g., crystalline or amorphous solids) that can be reconstitutedto provide liquid dosage forms suitable for parenteral administration toa subject.

The composition, shape, and type of dosage forms provided herein willtypically vary depending on their use. For example, a dosage form usedin the initial treatment of disease may contain larger amounts of one ormore of the active ingredients it comprises than a dosage form used inthe maintenance treatment of the same infection. Similarly, a parenteraldosage form may contain smaller amounts of one or more of the activeingredients it comprises than an oral dosage form used to treat the samedisease or disorder. These and other ways in which specific dosage formsencompassed herein will vary from one another will be readily apparentto those skilled in the art. See, e.g., Remington: The Science andPractice of Pharmacy, 21^(st) edition, Lippincott, Williams and Wilkins,Baltimore, Md. (2005), the contents of which are hereby incorporated byreference in their entirety.

Generally, the ingredients of compositions provided herein are suppliedeither separately or mixed together in unit dosage form, for example, asa dry lyophilized powder or water free concentrate in a hermeticallysealed container such as an ampoule or sachette indicating the quantityof active agent. Where the composition is to be administered byinfusion, it can be dispensed with an infusion bottle containing sterilepharmaceutical grade water or saline. Where the composition isadministered by injection, an ampoule of sterile water for injection orsaline can be provided so that the ingredients may be mixed prior toadministration.

Typical dosage forms provided herein comprise SNS-595 within the rangeof about 1 mg to about 150 mg per vial. Particular dosage forms providedherein have about 1, 3, 6, 9, 10, 12, 13.5, 15, 18, 19, 21, 24, 25, 27,30, 38, 45, 50, 60, 63, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120,125, 130, 135, 140, 145 or 150 mg of SNS-595 per vial.

5.5.1 Parental Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. Becausetheir administration typically bypasses patients' natural defensesagainst contaminants, parenteral dosage forms are preferably sterile orcapable of being sterilized prior to administration to a patient.Examples of parenteral dosage forms include, but are not limited to,solutions ready for injection, dry products ready to be dissolved orsuspended in a pharmaceutically acceptable vehicle for injection,suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage formsare well known to those skilled in the art. Examples include, but arenot limited to: Water for Injection USP; aqueous vehicles such as, butnot limited to, Sodium Chloride Injection, Ringer's Injection, DextroseInjection, Dextrose and Sodium Chloride Injection, and Lactated Ringer'sInjection; water-miscible vehicles such as, but not limited to, ethylalcohol, polyethylene glycol, and polypropylene glycol; and non-aqueousvehicles such as, but not limited to, corn oil, cottonseed oil, peanutoil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms. For example, cyclodextrin and its derivativescan be used to increase the solubility of active ingredients. See, e.g.,U.S. Pat. No. 5,134,127, which is incorporated herein by reference.

5.6 Exemplary Dosages

In one embodiment, the methods of treating, preventing or managingcancers provided herein comprise administering to a patient SNS-595and/or a pharmaceutically acceptable salt, solvate or hydrate thereof incombination with a second active agent, on the basis of body surfacearea. Body surface area calculations can be calculated for example, withthe Mosteller formula wherein:

BSA(m²)=square root of [(height(cm)×weight(kg)/3600].

In one embodiment, SNS-595 and/or a pharmaceutically acceptable salt,solvate or hydrate thereof can be administered orally or intravenouslyand in single or divided daily doses in an amount of about 1 to about150 mg/m². Certain exemplary doses per day include about 1, 3, 6, 9, 10,12, 13.5, 15, 18, 19, 21, 24, 25, 27, 30, 38, 45, 50, 60, 63, 75, 80,85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145 or 150mg/m².

In another embodiment, the methods comprise administering a dose ofabout 3 mg/m²-120 mg/m² of SNS-595 and/or a pharmaceutically acceptablesalt, solvate or hydrate thereof. In another embodiment, the dose isabout 10 mg/m²-100 mg/m². In another embodiment, the dose is about 30mg/m²-75 mg/m². In another embodiment, the dose is about 40 mg/m²-80mg/m². In another embodiment, the dose is about 50 mg/m²-90 mg/m². Inanother embodiment, the dose is about 15 mg/m²-80 mg/m².

In another embodiment the dose of SNS-595 and/or a pharmaceuticallyacceptable salt, solvate or hydrate thereof is about 20 mg/m²-30 mg/m².In another embodiment the dose is about 25 mg/m²-35 mg/m². In anotherembodiment the dose is about 40 mg/m²-50 mg/m². In another embodimentthe dose is about 45 mg/m²-55 mg/m². In another embodiment the dose isabout 50 mg/m²-60 mg/m². In another embodiment the dose is about 55mg/m²-65 mg/m². In another embodiment the dose is about 60 mg/m²-70mg/m². In another embodiment the dose is about 65 m g/m²-75 mg/m². Inanother embodiment the dose is about 70 mg/m²-80 mg/m². In anotherembodiment the dose is about 75 mg/m²-85 mg/m². In another embodimentthe dose is about 80 mg/m²-90 mg/m². In another embodiment the dose isabout 85 mg/m²-95 mg/m². In another embodiment the dose is about 90mg/m²-100 mg/m². In another embodiment the dose is about 100 mg/m²-110mg/m². In another embodiment the dose is about 110 mg/m²-120 mg/m². Inanother embodiment the dose is about 120 mg/m²-130 mg/m².

In another embodiment, the dose of SNS-595 and/or a pharmaceuticallyacceptable salt, solvate or hydrate thereof is about 1 mg/m²-75 mg/m².In another embodiment, the dose is about 1 mg/m²-60 mg/m². In anotherembodiment, the dose is about 1 mg/m²-48 mg/m². In another embodiment,the dose is about 3 m g/m²-24 mg/m².

In another embodiment, the dose is about 3 mg/m²-18 mg/m². In anotherembodiment, the dose is about 3 mg/m²-15 mg/m².

In another embodiment, the dose of SNS-595 and/or a pharmaceuticallyacceptable salt, solvate or hydrate thereof is about 1 mg/m², 2 mg/m², 3mg/m², 4 mg/m², 5 mg/m², 6 mg/m², 7 mg/m², 8 mg/m², 9 mg/m², 10 mg/m²,11 mg/m², 12 mg/m², 13 mg/m², 14 mg/m², 15 mg/m², 16 mg/m², 17 mg/m², 18mg/m², 19 mg/m², 20 mg/m², 21 mg/m², 22 mg/m², 23 mg/m², 24 mg/m², 25mg/m², 26 mg/m², 27 mg/m² , 28 mg/m², 29 mg/m², 30 mg/m², 31 mg/m², 32mg/m², 33 mg/m², 34 mg/m², 35 mg/m², 36 mg/m², 37 mg/m², 38 mg/m², 39mg/m², 40 mg/m², 41 mg/m², 42 mg/m², 43 mg/m², 44 mg/m², 45 mg/m², 46mg/m², 47 mg/m², 48 mg/m², 49 mg/m², 50 mg/m², 55 mg/m², 60 mg/m², 65mg/m², 75 mg/m² or 90 mg/m².

The administered dose of SNS-595 and/or a pharmaceutically acceptablesalt, solvate or hydrate thereof can be delivered as a single dose (e.g.a single bolus IV injection) or over a 24-hour period (e.g., continuousinfusion over time or divided bolus doses over time) and is repeateduntil the patient experiences stable disease or regression, or until thepatient experiences disease progression or unacceptable toxicity. Stabledisease or lack thereof is determined by methods known in the art, suchas evaluation of patient symptoms, physical examination and othercommonly accepted evaluation modalities.

The administered dose of SNS-59 and/or a pharmaceutically acceptablesalt, solvate or hydrate thereof 5 can be expressed in units other thanas mg/m². For example, doses can be expressed as mg/kg. One of ordinaryskill in the art would readily know how to convert doses from mg/m² tomg/kg to given either the height or weight of a subject or both (see,e.g, www.fda.gov/cder/cancer/animalframe.htm). For example, a dose of 10mg/m²-150 mg/m² for a 65 kg human is approximately equal to 0.26mg/kg-3.95 mg/kg. In another example, a dose of 15 mg/m²-80 mg/m² for a65 kg human is approximately equal to 0.39 mg/kg-2.11 mg/kg.

In certain embodiments, SNS-595 and/or a pharmaceutically acceptablesalt, solvate or hydrate thereof is cyclically administered to apatient. Cycling therapy involves the administration of an active agentfor a period of time, followed by a rest for a period of time, andrepeating this sequential administration. Cycling therapy can reduce thedevelopment of resistance to one or more of the therapies, avoid orreduce the side effects of one of the therapies, and/or improves theefficacy of the treatment.

In one embodiment, the methods provided herein comprise: i)administering a dose of about 10 mg/m²-120 mg/m² of SNS-595 and/or apharmaceutically acceptable salt, solvate or hydrate thereof to amammal; ii) waiting a period of at least one day where the mammal is notadministered any SNS-595 and/or a pharmaceutically acceptable salt,solvate or hydrate thereof; iii) administering another dose of about 10mg/m²-120 mg/m² of SNS-595 and/or a pharmaceutically acceptable salt,solvate or hydrate thereof to the mammal; and, iv) repeating stepsii)-iii) a plurality of times.

In one embodiment, the methods provided herein comprise: i)administering a dose of about 10 mg/m²-90 mg/m² of SNS-595 and/or apharmaceutically acceptable salt, solvate or hydrate thereof to amammal; ii) waiting a period of at least one day where the mammal is notadministered any SNS-595 and/or a pharmaceutically acceptable salt,solvate or hydrate thereof iii) administering another dose of about 10mg/m²-90 mg/m² of SNS-595 and/or a pharmaceutically acceptable salt,solvate or hydrate thereof to the mammal; and, iv) repeating stepsii)-iii) a plurality of times.

In one embodiment, the methods provided herein comprise: i)administering a dose of about 10 mg/m²-70 mg/m² of SNS-595 and/or apharmaceutically acceptable salt, solvate or hydrate thereof to amammal; ii) waiting a period of at least one day where the mammal is notadministered any SNS-595 and/or a pharmaceutically acceptable salt,solvate or hydrate thereof; iii) administering another dose of about 10mg/m²-70 mg/m² of SNS-595 and/or a pharmaceutically acceptable salt,solvate or hydrate thereof to the mammal; and, iv) repeating stepsii)-iii) a plurality of times

In one embodiment, the dose SNS-595 and/or a pharmaceutically acceptablesalt, solvate or hydrate thereof is about 15 mg/m² once a week for threeweeks. In one embodiment, the dose SNS-595 and/or a pharmaceuticallyacceptable salt, solvate or hydrate thereof is about 18 mg/m² once aweek for three weeks. In one embodiment, the dose SNS-595 and/or apharmaceutically acceptable salt, solvate or hydrate thereof is about 48mg/m² once every three weeks. In one embodiment, the dose SNS-595 and/ora pharmaceutically acceptable salt, solvate or hydrate thereof is about60 mg/m² once every three weeks. In one embodiment, the dose SNS-595and/or a pharmaceutically acceptable salt, solvate or hydrate thereof isabout 90 mg/m² once every three weeks.

5.6.1 Exemplary Dosages: Combination Dosing of SNS-595 and Second Agents

The methods provided herein comprise administering SNS-595 and/or apharmaceutically acceptable salt, solvate or hydrate thereof incombination with one or more second active agents selected fromcarboplatin, cisplatin and gemcitabine. The second agents providedherein can be administered either prior to, concurrently with, orsubsequent to administration of SNS-595 and/or a pharmaceuticallyacceptable salt, solvate or hydrate thereof. In some embodiments, thesecond agent can be administered subcutaneously or intravenously. Incertain embodiments, the second agent is administered subcutaneously. Incertain embodiments, the second agent is administered intravenously.

Combination of SNS-595 and Cisplatin

In one embodiment, the second agent is cisplatin and the dose ofcisplatin is about 5 mg/m² to about 200 mg/m², about 5 mg/m² to about150 mg/m², about 10 mg/m² to 100 mg/m², about 20 mg/m²to 80 mg/m², about50 mg/m² to 70 mg/m² or about 75 mg/m² to 100 mg/m². In anotherembodiment, the dose of cisplatin is about 20 mg/m². In anotherembodiment, the dose of cisplatin is about 75 mg/m² to 100 mg/m². Incertain embodiments, cisplatin can be administered continuously, bybolus injection, or by divided bolus injections over a particular timeperiod such as, for example, one day.

In some embodiments, the methods of treating cancer compriseadministering from about 1 mg/m² to about 150 mg/m² of SNS-595 and about20 mg/m² to about 100 mg/m² of cisplatin. In certain embodiments, themethods comprise administering about 10 mg/m² SNS-595 and about 20 mg/m²of cisplatin; about 15 mg/m² SNS-595 and about 18 mg/m² of cisplatin;about 30 mg/m² SNS-595 and about 20 mg/m² of cisplatin; about 48 mg/m²SNS-595 and about 20 mg/m² of cisplatin; about 60 mg/m² SNS-595 andabout 20 mg/m² of cisplatin; about 75 mg/m² SNS-595 and about 20 mg/m²of cisplatin; or about 90 mg/m² SNS-595 and about 20 mg/m² of cisplatin.

In certain embodiments, the methods comprise administering about 10mg/m² SNS-595 and from about 50 to 70 mg/m² of cisplatin; about 15 mg/m²SNS-595 and from about 50 to 70 mg/m² of cisplatin; about 30 mg/m²SNS-595 and from about 50 to 70 mg/m² of cisplatin; about 48 mg/m²SNS-595 and from about 50 to 70 mg/m² of cisplatin; about 60 mg/m²SNS-595 and from about 50 to 70 mg/m² of cisplatin; about 75 mg/m²SNS-595 and from about 50 to 70 mg/m² of cisplatin; or about 90 mg/m²SNS-595 and from about 50 to 70 mg/m² of cisplatin.

In certain embodiments, the methods comprise administering about 10mg/m² SNS-595 and from about 75 to 100 mg/m² of cisplatin; about 15mg/m² SNS-595 and from about 75 to 100 mg/m² of cisplatin; about 18mg/m² SNS-595 and from about 75 to 100 mg/m² of cisplatin; about 48mg/m² SNS-595 and from about 75 to 100 mg/m² of cisplatin; about 60mg/m² SNS-595 and from about 75 to 100 mg/m² of cisplatin; about 75mg/m² SNS-595 and from about 75 to 100 mg/m² of cisplatin; or about 90mg/m² SNS-595 and from about 75 to 100 mg/m² of cisplatin.

In certain embodiments, the methods of treating, preventing or managinga cancer comprises administering a total dosage of about 10 mg/m² -120mg/m² SNS-595, in one embodiment, about 10-80 mg/m² SNS-595 incombination with a continuous intravenous dose of about 5 mg/m² /day-30mg/m²/day if cisplatin for 5 days, in one embodiment, about 20 mg/m²/dayof cisplatin for a 5 day period, wherein the 5-day period comprises atreatment cycle. In some embodiments, the method comprises administeringa total dosage of about 20 mg/m²-60 mg/m² SNS-595 in combination with acontinuous intravenous dose of about 20 mg/m²/day cisplatin over a 5-dayperiod, wherein the 5-day period comprises a treatment cycle. In someembodiments, the treatment cycle is repeated at least once. In someembodiments, the treatment cycle is repeated at least twice. In someembodiments, the treatment cycle is repeated at least three times. Insome embodiments, the treatment cycle is repeated at least four times.

In certain embodiments, the methods of treating, preventing, or managinga cancer comprises administering a total weekly amount of about 10-120mg/m² SNS-595 in combination with a total daily amount of about 10-50mg/m² cisplatin.

In certain embodiments, cisplatin is administered at a dose of about 50to 70 mg/m² IV per cycle once every 3 to 4 weeks. In certainembodiments, cisplatin is administered at a dose of about 75 to 100mg/m² IV per cycle once every 4 weeks.

Combination of SNS-595 and Carboplatin

In one embodiment, the second agent is carboplatin and the dose ofcarboplatin is about 50 mg/m² to about 400 mg/m², about 100 mg/m² toabout 360 mg/m², about 150 mg/m² to 360 mg/m², about 200 mg/m² to 360mg/m², about 250 mg/m² to 360 mg/m² or about 300 mg/m²to 360 mg/m². Inanother embodiment, the dose of carboplatin is about 300 mg/m². Inanother embodiment, the dose of carboplatin is about 360 mg/m². Incertain embodiments, carboplatin can be administered continuously, bybolus injection, or by divided bolus injections over a particular timeperiod such as, for example, one day.

In some embodiments, the methods of treating cancer compriseadministering from about 1 mg/m² to about 150 mg/m² of SNS-595 and about300 mg/m² of carboplatin. In certain embodiments, the methods compriseadministering about 10 mg/m² SNS-595 and about 300 mg/m² of carboplatin;about 15 mg/m² SNS-595 and about 300 mg/m² of carboplatin; about 18mg/m² SNS-595 and about 300 mg/m² of carboplatin; about 48 mg/m² SNS-595and about 300 mg/m² of carboplatin; about 60 mg/m² SNS-595 and about 300mg/m² of carboplatin; about 75 mg/m² SNS-595 and about 300 mg/m² ofcarboplatin; or about 90 mg/m² SNS-595 and about 300 mg/m² ofcarboplatin.

In some embodiments, the methods of treating cancer compriseadministering from about 1 mg/m² to about 150 mg/m² of SNS-595 and about360 mg/m² of carboplatin. In certain embodiments, the methods compriseadministering about 10 mg/m² SNS-595 and about 360 mg/m² of carboplatin;15 mg/m² SNS-595 and abut 360 mg/m² of carboplatin; 18 mg/m² SNS-595 andabout 360 mg/m² of carboplatin; about 48 mg/m² SNS-595 and about 360mg/m² of carboplatin; about 60 mg/m² SNS-595 and about 360 mg/m² ofcarboplatin; about 75 mg/m² SNS-595 and about 360 mg/m² of carboplatin;or about 90 mg/m² SNS-595 and about 360 mg/m² of carboplatin.

In certain embodiments, the methods of treating, preventing or managinga cancer comprise administering a total dosage of about 10 mg/m² -120mg/m² SNS-595, in one embodiment, about 10-80 mg/m² SNS-595 incombination with a continuous intravenous dose of about 300 mg/m² ofcarboplatin once every 4 weeks. In certain embodiments, the methods oftreating, preventing or managing a cancer comprise administering a totaldosage of about 10 mg/m² -120 mg/m² SNS-595, in one embodiment, about10-80 mg/m² SNS-595 in combination with a continuous intravenous dose ofabout 360 mg/m² of carboplatin once every 4 weeks, wherein the 4 weekperiod comprises a treatment cycle. In some embodiments, the treatmentcycle is repeated at least once. In some embodiments, the treatmentcycle is repeated at least twice. In some embodiments, the treatmentcycle is repeated at least three times. In some embodiments, thetreatment cycle is repeated at least four times. In some embodiments,the treatment cycle is repeated at least six times.

Combination of SNS-595 and Gemcitabine

In one embodiment, the second agent is gemcitabine and the dose ofgemcitabine is about 100 mg/m² to about 1500 mg/m², about 500 mg/m² toabout 1500 mg/m², about 1000 mg/m² to about 1500 mg/m², about 1000 mg/m²to about 1400 mg/m² and about 1000 to about 1250 mg/m². In anotherembodiment, the dose of gemcitabine is about 1000 mg/m². In anotherembodiment, the dose of gemcitabine is about 1250 mg/m². In certainembodiments, gemcitabine can be administered continuously, by bolusinjection, or by divided bolus injections over a particular time periodsuch as, for example, one day.

In some embodiments, the methods of treating cancer compriseadministering from about 1 mg/m² to about 150 mg/m² of SNS-595 and about100 mg/m² to about 1500 mg/m² of gemcitabine. In certain embodiments,the methods comprise administering about 10 mg/m² SNS-595 and about 1000mg/m² of gemcitabine; about 15 mg/m² SNS-595 and about 1000 mg/m² ofgemcitabine; about 18 mg/m² SNS-595 and about 1000 mg/m² of gemcitabine;about 48 mg/m² SNS-595 and about 1000 mg/m² of gemcitabine; about 60mg/m² SNS-595 and about 1000 mg/m² of gemcitabine; about 70 mg/m²SNS-595 and about 1000 mg/m² of gemcitabine; about 75 mg/m² SNS-595 andabout 1000 mg/m² of gemcitabine; about 80 mg/m² SNS-595 and about 1000mg/m² of gemcitabine; about 90 mg/m² SNS-595 and about 1000 mg/m² ofgemcitabine; about 100 mg/m² SNS-595 and about 1000 mg/m² ofgemcitabine.

In certain embodiments, the methods comprise administering about 10mg/m² SNS-595 and about 1250 mg/m² of gemcitabine; about 15 mg/m²SNS-595 and about 1250 mg/m² of gemcitabine; about 18 mg/m² SNS-595 andabout 1250 mg/m² of gemcitabine; about 48mg/m² SNS-595 and about 1250mg/m² of gemcitabine; about 60 mg/m² SNS-595 and about 1250 mg/m² ofgemcitabine; about 70 mg/m² SNS-595 and about 1250 mg/m² of gemcitabine;about 75 mg/m² SNS-595 and about 1250 mg/m² of gemcitabine; 80 mg/m²SNS-595 and 1250 mg/m² of gemcitabine; 90 mg/m² SNS-595 and about 1250mg/m² of gemcitabine; about 90 mg/m² SNS-595 and about 1250 mg/m² ofgemcitabine.

In certain embodiments, the methods of treating, preventing or managinga cancer comprises administering a total dosage of about 10 mg/m² -100mg/m² SNS-595, in one embodiment, about 10-80 mg/m² in combination witha continuous intravenous dose of about 1000 mg/m² or 1250 mg/m² ofgemcitabine once a week for up to 7 weeks. In some embodiments, themethod comprises administering a total dosage of about 20 mg/m²-60 mg/m²SNS-595 in combination with a continuous intravenous dose of about 1000or 1250 mg/m² gemcitabine once a week for up to 4 weeks.

Duration (interval) between repeated administrations of the schedulescan range from about 1 week to 8 weeks after the end of the schedule. Inanother embodiment, the interval is from 3 weeks to 6 weeks.

5.6.2 Exemplary Dosing Schedules of SNS-595 and Second Agents

In the embodiments of the present invention, SNS-595 and the secondagents provided herein can be administered according to any scheduledeemed suitable by a practitioner of skill in the art. Provided in thissection are exemplary dosing schedules of SNS-595 in combination withthe second agents that can be practiced in the methods provided herein.

In certain embodiments, SNS-595 and/or a pharmaceutically acceptablesalt, solvate or hydrate thereof and the second agents are administeredin cycles. In certain embodiments, SNS-595 and the second agents areadministered in at least one cycle. In certain embodiments, SNS-595 andthe second agents are administered in at least two cycles. In certainembodiments, SNS-595 and the second agents are administered in at leastthree cycles. In certain embodiments, SNS-595 and the second agents areadministered in at least four cycles. In certain embodiments each cycleis at least 28 days. In one embodiment, the second agent is cisplatin.In one embodiment, the second agent is carboplatin. In one embodiment,the second agent is gemcitabine.

In certain embodiments, as discussed above, the initial dose of SNS-595is administered before the administration of the second agent. Incertain embodiments, the initial dose of SNS-595 is administeredimmediately before the administration of the second agent. In certainembodiments, administration of the second agent is initiated 1, 2, 3, 4,8, 12, 16, 24, or 32 hours following administration of SNS-595, forinstance, 1, 2, 3, 4, 8, 12, 16, 24, or 32 hours following completion ofthe administration of SNS-595.

6. EXAMPLES

Certain embodiments of the invention are illustrated by the followingnon-limiting example.

Example 1 Pharmaceutical Composition Suitable for Injection orIntravenous Infusion

Acidic compositions (<pH 4) provided the appropriate balance ofincreased solubility of SNS-595 and desirable pharmaceutical properties(e.g. increased patient comfort by causing less irritation at thedelivery site). An illustrative example of a suitable compositioncomprises: 10 mg SNS-595 per mL of aqueous solution of 4.5% sorbitolthat is adjusted to pH 2.5 with methanesulfonic acid. One protocol formaking such a solution includes the following for making a 100 mg/10 mLpresentation: 100 mg of SNS-595 and 450 mg D-sorbitol are added todistilled water; the volume is brought up to a volume of 10 mL; and thepH of the resulting solution is adjusted to 2.5 with methanesulfonicacid. The resulting composition is also suitable for lyophilization. Thelyophilized form is then reconstituted with sterile water to theappropriate concentration prior to use.

Example 2 SNS-595 in Combination with Cisplatin

The effect of co-administration of SNS-595 and cisplatin was observed onthe growth of ovarian carcinoma studied in athymic nude mice bearingsubcutaneous A2780 xenografts. The mice were treated with SNS-595,cisplatin or the two in combination as indicated below.

TABLE 1 Dose Dose Group N Compound (mg/kg) Route Schedule Compound(mg/kg) Route Schedule 1 10 Vehicle 0 IV qw x3 Vehicle 0 IP qw x3 2 10SNS-595 10 IV qw x3 3 10 Cisplatin 5 IP qw x3 4 10 SNS-595 10 IV qw x3Cisplatin 5 IP qw x3

Animal treatment was initiated when mean tumor volume was 200 mm³. Thecombination was co-dosed once a week for three weeks. Tumor volumes andanimal body weight were measured twice weekly. The data for body weightloss, % tumor growth inhibition and tumor growth delays in the animalsis shown in Table 2.

TABLE 2 % Tumor BW Nadir Growth Inhibition Tumor Growth Group (Day of)(Day 11) Delay (days) SNS-595  −4.7% 21.7% 5.5 10 mg/k qw × 3 (Day 4) (p > 0.05) Cisplatin −10.9% 49.0% 11.0  5 mg/kg qw × 3 (Day 11) (p <0.05) Combination −14.1% 64.2% 14.0 (Day 11) (p < 0.05)

Animals treated with SNS-595 alone (10 mg/kg qw ×3) had a tumor growthinhibition of 21.7% while those treated with cisplatin alone (5 mg/kg qw×3) had 49% tumor growth inhibition. When SNS-595 (10 mg/kg qw ×3) wascombined with cisplatin (5 mg/kg qw ×3) the tumor growth inhibitionincreased to 64.2%. Animals treated with the combination had a mean bodyweight loss of 14% with the nadir occurring on day 11. The effect of thetreatment on the tumor volume, % body weight change and % survival isprovided in FIGS. 1, 2 and 3, respectively. The survival of the micetreated with the combination of SNS-595 and cisplatin was increasedcompared to the vehicle or either single agent.

Example 3 SNS-595 in Combination with Carboplatin

The effect of co-administration of SNS-595 and carboplatin was observedon the growth of non-small cell lung carcinoma, athymic nude micebearing subcutaneous H460. The mice were treated with SNS-595,carboplatin or the two in combination as indicated below.

TABLE 3 Dose Dose Group N Compound (mg/kg) Route Schedule Compound(mg/kg) Route Schedule 1 10 Untreated 2 10 SNS-595 10 IV qw x5 3 10Carboplatin 75 IP qw x3 4 10 SNS-595 10 IV qw x5 Carboplatin 75 IP qw x3

Animal treatment was initiated when mean tumor volume was 200 mm³. Thecombination was co-dosed once a week for three weeks. Tumor volumes andanimal body weight were measured twice weekly. The data for body weightloss, % tumor growth inhibition and tumor growth delays in the animalsis shown in Table 4.

TABLE 4 % Tumor BW Nadir Growth Inhibition Tumor Growth Group (Day of)(Day 16) Delay (days) SNS-595 −0.7% 53.2% 23.0 10 mg/kg qw × 5 (Day 4)  (p > 0.05) Carboplatin −2.8% 31.6% 12.5 75 mg/kg qw × 3 (Day 16) (p >0.05) Combination −7.9% 74.6% 23.0 (Day 20) (p < 0.05)

Animals treated with SNS-595 alone (10 mg/kg qw ×5) had a tumor growthinhibition of 53% while those treated with carboplatin alone (75 mg/kgqw ×3) had 32% tumor growth inhibition. When SNS-595 (10 mg/kg qw ×5)was combined with carboplatin (75 mg/kg qw ×3) the tumor growthinhibition increased to 75%. Animals treated with the combination had amean body weight loss of 8%. This weight loss was recoverable andacceptable for the combination treatment. The effect of the treatment onthe tumor volume, % body weight change and % survival is provided inFIGS. 5, 6 and 7, respectively. The survival of mice treated with thecombination of SNS-595 and carboplatin was increased compared to thosetreated with carboplatin alone.

Example 4 SNS-595 in Combination with Gemcitabine

The effect of co-administration of SNS-595 and gemcitabine on the growthof non-small cell lung carcinoma, athymic nude mice bearing subcutaneousH460 xenografts were treated with SNS-595, gemcitabine or the two incombination as indicated below.

TABLE 5 Dose Dose Group N Compound (mg/kg) Route Schedule Compound(mg/kg) Route Schedule 1 10 Vehicle 0 IV qw x3 Vehicle 0 IP biw x2 24 hpost IV 2 10 SNS-595 10 IV qw x3 3 10 Gemcitabine 75 IP biw x2 4 10SNS-595 10 IV qw x3 Gemcitabine 75 IP biw x2

Animal treatment was initiated when mean tumor volume was greater than200 mm³. SNS-595 was administered once a week and gemcitabine was twiceweekly as indicated above with the combination being co-dosed. In thevehicle group, the gemcitabine vehicle was administered 24 hours afterthe SNS-595 vehicle representing additional treatment arms in theexperiment. Tumor volume and animal body weight was measured at leasttwice weekly. The data for body weight loss, % tumor growth inhibitionand tumor growth delays in the animals is shown in Table 6.

TABLE 6 % Tumor BW Nadir Growth Inhibition Tumor Growth Group (Day of)(Day 11) Delay (days) SNS-595 −5.9% 61.9% 11.0 10 mg/kg qw × 3 (Day 11)(p < 0.05) Gemcitabine −7.4% 36.6% 5.0 75 mg/kg Biw × 2 (Day 11) (p >0.05) Combination −7.9% 81.7% 51.0 (Day 18) (p < 0.01)

Animals treated with SNS-595 alone (10 mg/kg qw ×3) had a tumor growthinhibition of 62% while those treated with gemcitabine alone (75 mg/kgbiw ×2) had 37% tumor growth inhibition. When SNS-595 (10 mg/kg qw ×3)was combined with gemcitabine (75 mg/kg biw ×2) the tumor growthinhibition increased to 82%. Animals treated with the combination had amean body weight loss of 8% with the nadir occurring on day 24. Thisweight loss was recoverable and acceptable for the combinationtreatment. The effect of the treatment on the tumor volume, % bodyweight change and % survival is provided in FIGS. 7, 8 and 9,respectively. The survival of mice treated with the combination ofSNS-595 and gemcitabine was increased compared to the vehicle or eithersingle agent.

Example 5 SNS-595 in Combination with Gemcitabine

The effect of co-administration of SNS-595 and gemcitabine on the growthof pancreatic carcinoma, NIH-III mice bearing subcutaneous BxPC-3xenografts were were treated with SNS-595, gemcitabine or the two incombination as follows.

TABLE 7 Dose Dose Group N Compound (mg/kg) Route Schedule Compound(mg/kg) Route Schedule 1 10 Vehicle 0 IV qw x3 Vehicle 0 IP biw x3 2 10SNS-595 15 IV qw x3 3 10 Gemcitabine 65 IP biw x3 4 10 SNS-595 15 IV qwx3 Gemcitabine 65 IP biw x3

Animal treatment was initiated when mean tumor volume was greater than250 mm³. SNS-595 was administered once a week and gemcitabine was twiceweekly for two weeks followed by one additional dose as indicated abovewith the combination being co-dosed. Tumor volume and animal body weightwas measured at least once weekly. SNS-595 was administered once a weekand gemcitabine was twice weekly for two weeks followed by oneadditional dose as indicated above with the combination being co-dosed.Tumor volume and animal body weight was measured at least once weekly.The data for body weight loss, % tumor growth inhibition and tumorgrowth delays in the animals is shown in Table 8.

TABLE 8 % Tumor BW Nadir Growth Inhibition Tumor Growth Group (Day of)(Day 38) Delay (days) SNS-595 −2.5% 25.9% 23.0 15 mg/kg qw × 3 (Day 11)(p > 0.05) Gemcitabine     0% 20.2% 12.5 65 mg/kg biw × 2 (Day 0)  (p >0.05) Combination −9.9% 71.6% x (Day 21) (p < 0.01)

Animals treated with SNS-595 alone (15 mg/kg qw ×3) had a tumor growthinhibition of 26% while those treated with gemcitabine alone (65 mg/kgbiw ×3) had 20% tumor growth inhibition. When SNS-595 (15 mg/kg qw ×3)was combined with gemcitabine (65 mg/kg biw ×3) the tumor growthinhibition increased to 72%. Animals treated with the combination had amean body weight loss of 10% with the nadir occurring on day 21 oftreatment. This weight loss was recoverable and acceptable for thecombination treatment. The effect of the treatment on the tumor volume,% body weight change and % survival is provided in FIGS. 10, 11 and 12,respectively. The survival of mice treated with the combination ofSNS-595 and gemcitabine was increased compared to the vehicle or eithersingle agent.

The embodiments described above are intended to be merely exemplary, andthose skilled in the art will recognize, or will be able to ascertainusing no more than routine experimentation, numerous equivalents ofspecific compounds, materials, and procedures. All such equivalents areconsidered to be within the scope of the invention and are encompassedby the appended claims.

1. A method of treating cancer comprising administering a dose of about1 mg/m² to about 150 mg/m² of(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid and/or a pharmaceutically acceptable salt or hydrate thereof and adose of about 5 mg/m² to about 200 mg/m² cisplatin.
 2. The method ofclaim 1, wherein the dose of(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid and/or a pharmaceutically acceptable salt or hydrate thereof isfrom about 10 mg/m² to about 90 mg/m².
 3. The method of claim 1, whereinthe dose of(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid and/or a pharmaceutically acceptable salt or hydrate thereof isabout 18 mg/m².
 4. The method of claim 1, wherein the dose of(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid and/or a pharmaceutically acceptable salt or hydrate thereof isabout 48 mg/m².
 5. The method of claim 1, wherein the dose of(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid and/or a pharmaceutically acceptable salt or hydrate thereof isabout 60 mg/m².
 6. The method of claim 1, wherein the dose of(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid and/or a pharmaceutically acceptable salt or hydrate thereof isabout 75 mg/m².
 7. The method of claim 1, wherein the dose of cisplatinis from about 20 mg/m² to about 100 mg/m². 8-18. (canceled)
 19. A methodof treating cancer comprising administering a dose of about 1 mg/m² toabout 150 mg/m² of(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid and/or a pharmaceutically acceptable salt or hydrate thereof and adose of about 50 mg/m² to about 400 mg/m² carboplatin.
 20. The method ofclaim 19, wherein the dose of(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid and/or a pharmaceutically acceptable salt or hydrate thereof isfrom about 10 mg/m² to about 90 mg/m².
 21. The method of claim 19,wherein the dose of(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid and/or a pharmaceutically acceptable salt or hydrate thereof isabout 18 mg/m².
 22. The method of claim 19, wherein the dose of(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid and/or a pharmaceutically acceptable salt or hydrate thereof isabout 48 mg/m².
 23. The method of claim 19, wherein the dose of(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid is about 60 mg/m².
 24. The method of claim 19, wherein the dose of(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid and/or a pharmaceutically acceptable salt or hydrate thereof isabout 75 mg/m². 25-27. (canceled)
 28. The method of claim 1, wherein thecancer is bladder cancer, breast cancer, cervical cancer, colon cancer,esophageal cancer, head and neck cancer, liver cancer, small cell lungcancer, non-small cell lung cancer, melanoma, myeloma, neuroblastoma,ovarian cancer, pancreatic cancer, prostate cancer, renal cancer,sarcoma, skin cancer, stomach cancer, testicular cancer, thyroid canceror uterine cancer.
 29. (canceled)
 30. The method of claim 1, wherein thecancer is relapsed, refractory or resistant to conventional therapy. 31.The method of claim 1, further comprising administering atherapeutically effective amount of another active agent or a supportcare therapy.
 32. The method of claim 31, wherein the other active agentis a therapeutic antibody that specifically binds to a cancer antigen,hematopoietic growth factor, cytokine, anti-cancer agent, antibiotic,cox-2 inhibitor, immunomodulatory agent, immunosuppressive agent,corticosteroid or a pharmacologically active mutant or derivativethereof.
 33. The method of claim 1, wherein(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid and/or a pharmaceutically acceptable salt or hydrate thereof isadministered once a week for three weeks.
 34. The method of claim 1,wherein(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid and/or a pharmaceutically acceptable salt or hydrate thereofthereof administered once every three weeks.
 35. The method of claim 1,wherein(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid and/or a pharmaceutically acceptable salt or hydrate thereofthereof is administered as an IV injection.